Causes of pain are known to include the cases where a tissue is damaged by a disease or injury so that an algesic substance is topically produced, and the cases wherein there is no direct factor such as noxious stimulus, but the pain is caused by dysfunction of nerve system or the like. Pain may be largely classified into 3 groups depending on the cause, that is, (1) nociceptive pain, (2) neuropathic pain and (3) psychogenic pain. The “nociceptive pain” is the pain caused by an external stimulus such as injury and the pain caused by a lesion in an internal tissue. Most of this type of pain is transient, which disappears when the underlying disease is cured, so that it is usually classified into acute pain. On the other hand, chronic pain is caused by dysfunction of central nervous system due to abnormality of a peripheral tissue or terminal portion of peripheral nerve, or due to damage of peripheral nerve, or caused by damage of central nervous system or psychologic mechanism. The above-mentioned neuropathic pain and the psychogenic pain belong to this chronic pain. Although pain is caused by various factors and its expression mechanism has not been well understood, reported endogenous substances related to pain and its regulation include bradykinin, histamine, prostaglandin, serotonin, substance P and opioid peptides.
As the therapeutic drugs against mild pain, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and acetaminophen, having a site of action in the periphery have been used. As the therapeutic drugs against moderate or severe pain, opioid analgesics typified by morphine, having a site of action in the central nervous system have been used. However, the peripheral analgesics such as NSAIDs have a problem in that they have a side effect against digestive, in addition to the fact that the analgesic effects thereof are not sufficient in some cases. The opioid analgesics have a problem in that they have side effects such as nausea, vomiting, constipation and dependence. Further, although the analgesics typified by morphine exhibit effects against acute pain, they do not exhibit sufficient effects against neuropathic pain and psychogenic pain in most cases. Thus, creation of a novel analgesic which is not only effective against acute pain, but also effective against the chronic pain for which morphine is not effective, of which side effect is small, is demanded.
It is known for a long time that morphinan compounds typified by morphine have analgesic effects. Even limiting the morphinan compounds to those having a nitrogen-containing cyclic group on the 6-position, it has already been suggested that cyclic secondary amino compounds have analgesic effect (see Japanese Patent Publication (Kokoku) S41-18824, Japanese Patent Publication (Kokoku) S41-18826 and International Patent Publication No. WO 95/03308). Further, chemical structures of some of the morphinan compounds having a cyclic imide group on the 6-position have been disclosed, although the analgesic activities thereof have not been directly disclosed (see Csaba Simon et al., Tetrahedron, 1994, Vol. 50, No. 32, pp. 9757-9768, L. M. Sayre et al., Journal of Medicinal Chemistry, 1984, Vol. 27, No. 10, pp. 1325-1335 and Csaba Simon et al., Synthetic Communications, 1992, Vol. 2, No. 6, pp. 913-921). On the other hand, separately from these, it has been disclosed that the compounds have therapeutic effects against frequent urination and urinary incontinence (see International Patent Publication No. WO 2004/033457 (European Patent Publication No. EP 1 555 266 A1). Their antipruritic activities have also been disclosed, although the date of disclosure is after the priority date of the present application (International Patent Publication No. WO 2005/094826). However, none of these disclosed information infer that the compounds may be used as valuable analgesics which have potent analgesic effects and which may also be applied to chronic pain.